Children with sickle cell anemia (SCA) in sub-Saharan Africa are at high risk to suffer from malaria. Other high-risk groups in Africa ? including pregnant women and infants ? are administered intermittent preventive therapy with antimalarials to reduce the burden of malaria, but strategies to do so in SCA children are lacking. Currently, few strategies have been tested, and none with large sample sizes powered on clinically-important outcomes for malaria and SCA. In this project, we propose a three-arm, randomized, active-placebo clinical trial of malaria chemoprophylaxis regimens in children with SCA in Western Kenya. Capitalizing on the clinical trial expertise of the Duke Clinical Research Institute, the global field research footprint of the Duke Global Health Institute, and existing collaborations with Moi University and partners in Western Kenya, we will enroll children with SCA in Homa Bay, Kenya, which is endemic for falciparum malaria. Children will be randomized to either daily Proguanil (current standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine, or monthly dihydroartemisinin-piperaquine, and followed for 12 months. The primary outcome will be the incidence of falciparum malaria, and other prespecified outcomes compared between allocation arms will be measures of SCA morbidity including painful events, dactylitis, and need for transfusion, measures of malaria severity, and hospitalizations and deaths. At the conclusion of the study, we expect to provide an evidence base for the use of two alternative strategies to protect children with SCA from malaria, and to potentially reduce the morbidity of SCA in malaria-endemic areas in Africa. These data will directly enable clinicians in Africa to improve the care of children with SCA.